The recent availability of a genetic test (homozygosity for the C282Y mutation in the HFE gene) for the diagnosis of hereditary hemochromatosis (HH) has focused renewed attention on this relatively common disorder. However, phlebotomy therapy in HH remains hampered by lack of simple, physiologic laboratory monitoring guides. In addition, phlebotomy therapy has been perceived as wasteful because the blood obtained is not used for allogeneic transfusion, although many HH subjects meet standards for allogeneic blood donation. Recent regulatory changes now allow increased flexibility in establishing policies for transfusion of blood obtained from HH subjects. We developed a protocol for use of the red cell mean corpuscular volume (MCV), a precisely measured indicator of erythopoietic iron availability, as a simple, physiologically based target to guide the pace of induction and maintenance phlebotomy for HH. We also developed a program to use blood therapeutically withdrawn from HH subjects for allogeneic transfusion. To enable the operational aspects of using HH donor blood for transfusion, a customized multi-user database program was developed as a Microsoft Access application to maintain and analyze lab data, generate a schedule of phlebotomy intervals and appointment dates, and notify staff when pre-set therapeutic endpoints were reached. We enrolled 60 patients with HH in the first year of this protocol. Induction phlebotomy to achieve iron depletion was performed every 1 to 4 weeks, depending on subject weight and initial ferritin levels, and continued until the MCV decreased by 3-5% below pretreatment baseline. A fingerstick hemoglobin (HGB) greater than 12.5 g/dL was used as the threshold for performing phlebotomy. Maintenance phlebotomy was targeted to maintain the red cell MCV at 3% below baseline, with weekly to monthly measurements of MCV, ferritin, and transferrin saturation (TS) to determine the rate of reaccumulation of iron. Median pre-treatment values in the first 27 previously untreated patients included ferritin 1039 (range 65-5248) ng/mL, transferrin saturation (TS) 80 (32-95)%, and MCV 96.3 (90-105) cubic microns. Median ferritin was 16 (5-47) ng/mL, TS was 11 (3-22)%, and HGB was 12.0 (10.9-13.3) g/dL at the point of transition from induction to maintenance therapy, as defined by the MCV guide. A mean of 19 induction bleeds were performed until iron-depletion was achieved. Nadir HGB levels of 11.7 (10.4-12.6) g/dL occurred 1.5 (0-4) wks after the transition to maintenance therapy. The mean iron removal necessary to maintain a stable ferritin, MCV and TS during maintenance therapy in 22 C282Y homozygotes was 50 ug/kg/day, was highly correlated with body weight, and was significantly higher in the C282Y homozygotes than in 5 C282Y/H63D compound heterozygotes, 33 ug/kg/day. Women and older subjects tolerated initial induction phlebotomy better at 2, rather than 1 week intervals. These data correspond to a stable maintenance interval of every 7 to 9 weeks for an 85 kg C282Y/C282Y homozygote, and every 10 to 12 weeks for a compound heterozygote of similar size using 500 mL whole blood phlebotomy and a targeted maintenance HGB of 14 g/dL. 33 of 55 (60%) of HH subjects had arthritis on entry, but there was no definite improvement in joint complaints with progressive iron depletion. Occurrence of arthritis was highly correlated with higher iron burden at presentation and with C282Y homozygosity. 46 (77%) of the HH subjects met donor eligibility criteria. During this period, 256 red cell units derived from HH subjects entered allogeneic inventory, constituting 6% of all allogeneic red cell collected at our center. Positive viral markers were found in 4 HH subjects, all of whom admitted deferrable risk prior to testing. Subjects expressed great satisfaction in knowing their blood was made available to others rather than discarded. Use of the red cell MCV provides an inexpensive, simple, and individualized parameter that is widely available and suitable for use to achieve optimal phlebotomy therapy. Our data indicate that serial MCV changes reliably indicate iron depletion, and can be used to avoid symptomatic anemia at the transition to maintenance phlebotomy. HH subjects can safely augment the allogeneic blood supply, leading to improvements in allogeneic inventory, in HH patient care, and in benefit to the community. Our data argue strongly for a comprehensive movement of HH phlebotomy care into the blood center. Phlebotomy can be simply and safely managed in this setting with the use of HGB and MCV-based guidelines.